The early age at retinoblastoma occurrence, the most common eye malignancy in childhood, suggests that perinatal factors may contribute to its etiology. Methods: In a large multicenter study of non-familial retinoblastoma, we conducted structured interviews with the parents of 280 cases and 146 controls to elicit information on health during the perinatal period.
Trang 1R E S E A R C H A R T I C L E Open Access
retinoblastoma in relation to maternal
health conditions and reproductive factors: a
Julia E Heck1*, Negar Omidakhsh1, Saeedeh Azary1, Beate Ritz1, Ondine S von Ehrenstein2, Greta R Bunin3
and Arupa Ganguly4
Abstract
Background: The early age at retinoblastoma occurrence, the most common eye malignancy in childhood,
suggests that perinatal factors may contribute to its etiology
Methods: In a large multicenter study of non-familial retinoblastoma, we conducted structured interviews with the parents of 280 cases and 146 controls to elicit information on health during the perinatal period We used unconditional logistic regression to assess associations between retinoblastoma and parental fertility treatment, birth control use in the year prior to pregnancy, maternal health conditions and the use of prescription medications during pregnancy, and whether mothers breastfed the index child
Results: Bilateral retinoblastoma was related to maternal underweight (body mass index <18.5) prior to pregnancy [Odds Ratio (OR) = 4.5, 95 % confidence interval (CI) 1.0, 20] With regards to unilateral retinoblastoma, we observed
a negative association with the use of condoms in the year prior to pregnancy (OR = 0.4, CI 0.2, 0.9), and a trend towards a positive association with maternal diabetes (OR = 2.2, CI 0.8, 6.6)
Conclusions: Results from our study suggest a role for several maternal health and reproductive factors Given that there are few epidemiologic studies of retinoblastoma, our results require replication in studies which utilize
medical record review
Key words: Retinoblastoma, Body mass index, Diabetes, Contraception, Condoms, Human papillomavirus, Fertility Agents, Acetaminophen, Risk Factors, Childhood Cancer Epidemiology
Background
Retinoblastoma is the most common intraocular
ma-lignancy in childhood, with an incidence of 11.8 per
million children aged 0–4 years in the United States
[1] It results from inactivation of both alleles of the
tumor suppressor RB1 gene When the disease is
gene mutation from a parent, and the other allele is
lost somatically The remaining cases of disease are
considered sporadic In 30 % of cases, the RB1 muta-tion in one allele occurs as a de novo mutamuta-tion in par-ental germline cells (usually of paternal origin [3]) or happens in very early embryonic development, and the other allele is lost somatically sometime after concep-tion In both of the above instances, retinoblastoma typically presents bilaterally In the remaining 60 % of cases, the disease results from two somatic alterations
in a retinal cell at some point after conception; these cases present as unilateral disease
Although little is known about the causes of sporadic retinoblastoma, there have been several studies that sug-gested a role for reproductive health factors A meta-analysis of four studies reported an increased risk for
* Correspondence: jeheck@ucla.edu
1 Department of Epidemiology, Fielding School of Public Health, University of
California, 650 Charles E Young Dr, Box 951772, Los Angeles, CA 90095-1772,
USA
Full list of author information is available at the end of the article
© 2015 Heck et al Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made The Creative Commons Public Domain Dedication waiver
Trang 2retinoblastoma among children conceived via assisted
reproductive technologies [4]; however, a recent study
did not support this association [5] Some, but not all,
epidemiologic and laboratory studies have suggested a
role for human papillomavirus (HPV) in retinoblastoma
[6–15] A study in Sweden found high but imprecisely
estimated increased risks of retinoblastoma with longer
breastfeeding, although a dose–response effect was not
evident [16]
Parental prescription drug use in pregnancy has been
of particular interest in cancer research ever since
Herbst and Ulfelder reported an association between
maternal use of diethylstilbestrol (DES) in pregnancy
and clear cell adenocarcinoma of the vagina in young
women [17] A number of childhood cancer studies have
examined the risk from maternal intake of medication
during pregnancy [18–20], however studies of
retino-blastoma are limited While one study observed the
prevalence of morning sickness to be the same among
retinoblastoma cases and controls [21], the use of
anti-nauseants was much higher among case mothers in a
different study [7]
The goal of the present study was to examine maternal
comorbidities, medication use during pregnancy, and
reproductive health related factors in relation to
retino-blastoma in offspring
Methods
We conducted a multi-center case–control study of
ret-inoblastoma across the USA and Canada from June 2006
to June 2011 [22] Children with sporadic retinoblastoma
were identified from Wills Eye Hospital in Philadelphia,
or by the Children’s Oncology Group (COG), which
in-cludes over 200 institutions in the USA and Canada
Each participating COG institution, Wills Eye Institute,
the University of Pennsylvania, and the University of
California, Los Angeles approved the study After a
physician gave his or her approval to contact a patient,
children were eligible for the present study if at least
one biological parent consented to participate, if they
re-sided in the continental U.S., Alaska, or Canada, if they
had a telephone in their household, and if at least one
parent spoke English or Spanish Children conceived
with a donor egg or sperm were eligible for the study
Participants provided written informed consent for
bios-pecimen collection; because interviews took place via
telephone, we collected verbal informed consent for the
interview, which was documented on the questionnaire
In total, 282 cases of retinoblastoma (187 unilateral and
95 bilateral cases) were enrolled in the study
The family of each case was asked to nominate one or
more children of their friends or non-blood relatives
under age 15 as potential controls For bilateral cases,
eligible control fathers were not a biological relative of
the case’s father; for unilateral cases, eligible control mothers were not a biological relative of the case’s mother
We attempted to match controls to cases on the child’s age at the time of interview (0–1, 2–4, 5–9, 10–14 years old) If more than one control was nominated by the case parents, we attempted to recruit the eligible control clos-est in age to the case If that control was not successfully recruited, we attempted to recruit the next control until
we obtained a control or until we contacted all potential controls When an“ideal control” (age-matched and not a biological relative) was unavailable, cases were asked to suggest another potential child as a control Some families did not nominate any child as a control or the control’s family did not consent to enroll in the study, therefore for some cases there was no matched control Overall, 155 controls were recruited
The majority (>90 %) of sporadic bilateral cases are due to a de novo mutation in the father’s germline [3] Therefore, for bilateral cases, we were most interested in paternal preconceptional exposures In contrast, because unilateral cases derive from two RB1 mutations which occur during pregnancy, for unilateral cases we were most interested in examining pregnancy exposures In a structured telephone interview with the parents, data
mother’s medical conditions in pregnancy, her repro-ductive history, and other exposures With regards to perinatal health conditions, mothers were asked several open-ended questions to prompt their memories about pregnancy-related and unrelated medical conditions which occurred in the month prior or during pregnancy,
as well as conditions that had been diagnosed before the pregnancy but for which they had received treatment during the pregnancy With regards to medications,
medi-cine for any condition, such as the flu, an infection, acci-dent or injury, in the month before or during your pregnancy?” Over-the-counter medications were not ascertained In total, 280 mothers of cases (185 unilateral and 95 bilateral) and 146 mothers of controls completed the interview When one parent was unavailable, the interview was conducted with a proxy who was typically the other parent, with 16.5 % of paternal and 3 % of ma-ternal interviews conducted by proxy
We used unconditional logistic regression to evaluate the risk of retinoblastoma Given that a number of cases had no matched control, we chose to use unconditional logistic regression in order to improve statistical power
We reported odds ratios (ORs) and 95 % confidence in-tervals (CIs) adjusted for mother’s race/ethnicity (White non-Hispanic, Black non-Hispanic, Hispanic, other), ma-ternal educational attainment (Less than high school, high school graduate, some college or other training, college graduate or more), household income (less than
Trang 3$35,000, $35,000 to 50,000, $50,000 to 75,000, more than
$75,000), the mother’s age at child’s birth (continuous),
and a behavioral indicator, the mother’s tobacco smoking
in the month before or during pregnancy (Yes/No) We
explored additional adjustment for marital status and
child’s gender however they did not change the estimates
by more than 10 %, and were not included in the final
model When statistical power allowed us to do so, we
checked our results in the matched analysis using
condi-tional logistic regression, adjusting for the same
covari-ates other than child’s age (matching variable)
Many health conditions were identified by only a small
number of mothers We provide results for which there
were at least 5 unilateral cases that reported having the
medical condition; in addition, because of the prior
re-ported associations between retinoblastoma and
infertil-ity treatment [4] as well as sexually transmitted diseases
[6], we reported associations with any sexually
transmit-ted disease and with the type of fertility treatment The
category“other viral infections” included hepatitis B and
C, shingles, HPV, herpes, stomach virus, Murray
infec-tion, and Fifth disease We defined hormonal birth
control methods as oral contraceptive pills, injection,
implant, skin patch, or vaginal ring The category“other
types of birth control” included diaphragm, cervical cap,
sponge, IUD, Lea’s shield, other barrier method,
vasec-tomy, tubal ligation, rhythm method, fertility awareness,
and withdrawal
We examined maternal and paternal weight prior to
pregnancy and pregnancy weight gain Based upon
recom-mendations issued by the Institute of Medicine [23], we
defined normal weight gain in pregnancy as 28–40 pounds
for underweight women [body mass index (BMI) < 18.5],
25–35 pounds for normal women (BMI = 18.5–25), 15–25
pounds for overweight women (BMI = 25–30) and 11–20
pounds for obese women (BMI > 30)
In models which evaluated retinoblastoma’s association
with birth control use, we adjusted for the same
vari-ables above except the mother’s age at child’s birth,
be-cause it did not change the point estimate by more than
10 % For analyses of fertility treatment, parity and
breast feeding, we utilized the same covariates in models
except for mother’s age at child’s birth and mother’s
tobacco smoking, because they did not change point
es-timates by more than 10 %
Because information for some covariates was missing
(primarily with regards to family income and maternal
smoking status during pregnancy) we conducted
sensi-tivity analyses in which we used multiple imputation
methods (“PROC MI and PROC MIANALYZE”) in SAS
9.2 to compensate for missing data In addition, due to
differences between case and control groups, we then
ana-lyzed our imputed dataset using propensity score
tech-niques where scores for all exposures were calculated
from a logistic regression model with each exposure from tables 2, 3 and 4 set as the dependent variable and all co-variates set as the independent variable Results from the multiple imputation/propensity score analyses did not dif-fer substantially from the main results, with most point es-timates and confidence intervals changing by <0.1–0.2 Thus, we present results from logistic regression in main tables; multiple imputation/propensity score analyses are presented in Additional file 1
We additionally conducted sensitivity analyses to examine whether results changed when we excluded the
3 % of maternal interviews that were conducted by proxy
Results
On average, bilateral cases were diagnosed at age 1.1 years [standard deviation (sd) = 0.9] and unilateral cases were diagnosed at age 2.0 years (sd = 1.7) Table 1 shows the demographic characteristics of participants Mothers of unilateral cases included more Hispanics or Blacks and fewer whites than mothers of controls Mothers of bilateral and unilateral cases had lower edu-cational attainment and income than control mothers There was also some indication that mothers of bilateral cases were older (35+ years old) during pregnancy than control mothers Moreover, mothers of both bilateral and unilateral cases were more likely to smoke in the month before or during pregnancy
Associations between maternal medical problems in the month before or during pregnancy and sporadic ret-inoblastoma development in their child are presented in Table 2; only a few mothers reported any of a number of conditions during pregnancy Few parents reported any sexually transmitted disease in pregnancy; reported in-fections included one case of HPV and one of herpes Reports of diabetes also showed increases in unilateral and bilateral retinoblastoma (OR = 2.2, CI 0.8, 6.6, and
OR = 1.9, CI 0.6, 6.6, respectively) Despite the low num-ber of exposed controls (N = 1), we did find a trend to-wards increased risk of unilateral retinoblastoma among mothers with anemia (OR = 2.8, CI 0.3, 27.0) Use of pre-scription pain medication in pregnancy was positively associated with unilateral and bilateral retinoblastoma development in the child (OR = 9.0, CI 1.4, 56.4), how-ever this association was tempered in multiple imput-ation/propensity score analyses (OR = 3.7, CI 0.9, 16.1)
In conditional logistic regression analyses, however, no association was observed for either unilateral (OR = 0.9,
CI 0.03, 26.3) nor bilateral (OR = 1.2, CI 0.1, 25.8) dis-ease Of the pain medications used, 12 mothers took acetaminophen, 3 took ibuprofen, 1 took tramadol, and the remaining 2 took an unspecified type of medication Mothers of both unilateral and bilateral cases reported more diabetes (OR = 2.2, CI 0.8, 6.6 using unconditional
Trang 4logistic regression; OR = 2.3, 95 % CI 0.9, 6.0 in
mul-tiple imputation/propensity score analyses) Mothers of
cases also reported more depression or anxiety
disor-ders (OR = 3.3, CI 0.7, 14.8, OR = 3.8, CI 0.7, 21.8) and
asthma/allergies (bilateral) (OR = 1.7, CI 0.5, 5.9) during
their pregnancy with their child than control mothers
Maternal underweight prior to pregnancy was
associ-ated with an increase in bilateral retinoblastoma
(Table 3), although results were lower in multiple
imput-ation/propensity score analyses In the conditional
analyses, maternal underweight was also positively
asso-ciated with unilateral retinoblastoma (OR = 4.0, 95 % CI
0.5, 31.5), while the association with bilateral disease was
not possible to estimate because there were no
under-weight case mothers We observed that breast feeding
decreased the risk of unilateral retinoblastoma, and this
protective effect was stronger for children who had been breast fed for 7–11 months However, no dose–response effect was observed with longer (12+ months) breast-feeding When we stratified by maternal education, we observed that longer breastfeeding was negatively associ-ated with retinoblastoma for mothers with a high school diploma or fewer years of education (OR = 0.2, CI 0.01, 1.6) and among mothers who had some schooling after high school but who had not graduated college (OR = 0.2, CI 0.008, 3.0) In contrast with the mothers with less formal education, breastfeeding was associated with in-creased risk among women with a college degree or more (OR = 2.6, CI 0.9, 8.0) In conditional logistic re-gression analyses, breastfeeding greater than 12 months was associated with a weak decreased risk (OR = 0.5, CI 0.1, 2.1)
The use of condoms for birth control prior to preg-nancy was associated with a lower risk of unilateral ret-inoblastoma in unconditional (OR, 0.4; CI 0.2–0.9; Table 4) and conditional analyses (OR = 0.1, CI 0.1, 0.9) There was a slightly increased risk for unilateral retino-blastoma and the use of any type of hormonal birth con-trol; this estimate did not change after additional adjustment for condom use Elevated point estimates, with wide confidence intervals, could be seen when examining the association with fertility treatment In conditional regression analyses, there was no association between the use of any type of fertility treatment and unilateral disease (OR = 0.9), however an increased risk for bilateral disease, with wide confidence intervals, was seen (OR = 2.4, CI 0.1, 20.2) The types of fertility treat-ment that were reported were In-Vitro Fertilization [IVF; 0 controls, 7 (3.8 %) unilateral cases, 5 (5.3 %) bi-lateral cases], Intra Cytoplasmic Sperm Injection [ICSI; 1 (0.7 %) controls, 3 (1.6 %) unilateral cases, 2 (2.1 %) bilateral cases], and artificial intra-uterine insemination [2 (1.4 %) controls, 3 (1.6 %) unilateral cases, 3 (3.2 %) bilateral cases] Of the participants that could not iden-tify the specific type of fertility treatment used, 2 con-trols, 2 unilateral cases, and 4 bilateral cases indicated it was due to a problem of the mother’s, while no controls,
3 unilateral cases, and 2 bilateral cases indicated it was due to a problem of the father’s It should be noted that the same families may have tried several different fertil-ity treatment methods
In sensitivity analyses which excluded proxy inter-views, we observed similar results to those seen in the overall study
Discussion This study is one of only a small number of investiga-tions into maternal health and reproductive health re-lated factors in relation to retinoblastoma We observed
a negative association for retinoblastoma with condom
Table 1 Demographic characteristics of mothers
Controls Unilateral cases Bilateral cases Characteristics (N = 146) (N = 185) (N = 95)
Mother ’s race
White non-Hispanic 111 (76) 105 (56.8) 66 (69.5)
Black non-Hispanic 5 (3.4) 14 (7.6) 3 (3.2)
Hispanic 18 (12.3) 46 (24.9) 12 (12.6)
Mother ’s educational
attainment
Less than High school 6 (4.1) 15 (8.1) 9 (9.5)
High school graduate 15 (10.3) 32 (17.3) 13 (13.7)
Some college or other
training
26 (17.8) 40 (21.6) 16 (16.8) College graduate or more 99 (67.8) 98 (53.0) 57 (60.0)
Mother ’s age at child’s birth
Total household income
Less than $35,000 29 (19.9) 56 (30.3) 27 (28.4)
$35,000 –50,000 19 (13.0) 18 (9.7) 11 (11.6)
$50,000 –75,000 30 (20.6) 30 (16.2) 18 (19.0)
More than $75,000 60 (41.1) 62 (33.5) 32 (33.7)
Refused/do not know 8 (5.5) 19 (10.3) 7 (7.4)
Mother smoked in the month
before or during pregnancy
Trang 5use in the year before pregnancy and an increased risk
with maternal underweight at the start of pregnancy and
when the mother took pain medication during pregnancy
For many self-reported health conditions, there were only
a small number of mothers who indicated that they had
had the condition in the perinatal period, thus we were
underpowered in many analyses Hence, results must be
interpreted with caution Although the small sample size
led to wide confidence intervals, we observed trends
to-wards increased risks with several maternal conditions
during pregnancy, including viral infections, diabetes,
de-pression or anxiety, and anemia Other studies examining
these conditions have found conflicting results [6, 7]
These findings require replication elsewhere, preferably in
studies which utilize medical record review
Maternal underweight prior to pregnancy is a well-recognized risk factor for a variety of adverse fetal outcomes such as intrauterine growth restriction [24], however there are only a few studies which examined it
in relation to childhood cancers Maternal underweight (BMI <20) was associated with a 40 % increase in hepa-toblastoma risk in one population-based study [25] Maternal undernutrition can alter fetal programming and potentially change specific cell groups or organogen-esis including the developing retina [26] Both animal and human studies have shown that fetal growth restric-tion can cause changes in retinal structure [27, 28] A role for specific nutrients in retinoblastoma prevention has been suggested, particularly for folate, an important methyl donor [21, 29]
Table 2 Retinoblastoma in relation to maternal medical conditions and prescription drug use
Controls (n = 136) Unilateral cases (n = 165) Bilateral cases (n = 87)
Crudea Adjustedb Crudea Adjustedb
Any medical condition 74 (47.7) 115 (61.5) 1.6 1.5 (0.9, 2.6) 57 (60.0) 1.6 1.2 (0.7, 2.3) Infectious diseases
Any infectious disease 32 (20.7) 44 (23.6) 1.1 1.0 (0.5, 1.7) 19 (20.0) 0.8 0.8 (0.4, 1.6) Respiratory infection 18 (11.6) 21 (11.2) 1.0 0.9 (0.4, 2.0) 7 (7.4) 0.5 0.4 (0.1, 1.2)
Other viral infections 1 (0.7) 5 (2.7) 3.8 3.6 (0.3, 47.9) 2 (2.1) 2.2 3.7 (0.3, 3.5)
-All bacterial infections 18 (11.6) 24 (12.8) 1.1 1.1 (0.5, 2.4) 11 (11.6) 0.9 0.8 (0.3, 2.1) Urinary tract infections 6 (3.9) 9 (4.8) 1.1 0.8 (0.2, 3.0) 1 (1.1) 0.1 0.2 (0.1, 1.8) Mother took antibiotics in pregnancy 21 (13.6) 22 (11.8) 0.8 0.8 (0.3, 1.8) 10 (10.5) 0.6 0.5 (0.2, 1.4) Chronic diseases
High blood pressure 17 (11.0) 23 (12.3) 1.1 1.2 (0.5, 2.6) 11 (11.6) 1.2 1.0 (0.4, 2.6) Gestational high blood pressure 17 (11.0) 22 (11.8) 1.1 1.1 (0.5, 2.5) 11 (11.6) 1.2 1.0 (0.4, 2.6)
Gestational diabetes 6 (3.9) 14 (7.5) 2.0 1.9 (0.6 5.7) 8 (8.4) 1.8 1.9 (0.6, 6.6)
Endocrine disorders
Pain and pain medication
Other Diseases and conditions
a Adjusted for the matching variable, child’s age at interview
b Adjusted for child age at interview, mother’s race/ethnicity, mother’s educational attainment, household income, mother’s age at birth, and maternal smoking in the month before or during pregnancy
Trang 6Our findings on condom use reinforce the observation
of an earlier study which reported that the use of barrier
conception in the year prior to pregnancy was associated
with lower risk of retinoblastoma [7] Given that the use
of condoms not only can prevent incident HPV
infec-tions but also may promote clearance of HPV in women
with a previously positive HPV test [30, 31], our results
support a possible role for HPV in retinoblastoma
devel-opment Vertical transmission of HPV would
presum-ably occur during passage of the fetus through the
birth canal [32] In a previous study, we observed a
weak lowered risk of unilateral retinoblastoma with Cesarean Section (OR=0.8) [6] In some but not all studies, HPV DNA has been isolated from retinoblast-oma tumor tissue [8–15] Contradictory findings across studies may be due to variation in the under-lying prevalence of HPV across regions, cofactors (dietary or behavioral) that may affect HPV behavior,
or specimen contamination The biological plausibility
of this association is supported by the well-known binding of HPV protein E7 to the tumor suppressor protein pRb, rendering it inactive [33]
Table 3 Associations between maternal pregnancy history, body size, and breastfeeding with retinoblastoma using unconditional logistic regression
Controls Unilateral cases (n = 165) Bilateral cases (n = 87)
Maternal history of stillbirth 1 (0.7) 5 (2.7) 4.8 2.1 (0.2, 20.9) 2 (2.1) 4.1 2.9 (0.2, 49.8) Order of index pregnancy
Second pregnancy 39 (27.1) 57 (31.0) 1.4 1.4 (0.8, 2.7) 32 (34.0) 1.6 1.8 (0.8, 3.8) Third and above 50 (34.7) 67 (36.4) 1.3 1.2 (0.7, 2.2) 29 (30.9) 1.1 1.2 (0.6, 2.4) Order of index child
Third and above 33 (22.9) 30 (16.3) 0.8 0.7 (0.4, 1.4) 20 (21.5) 1.1 1.1 (0.5, 2.5) Ever breastfed index child 120 (85.1) 137 (74.9) 0.5 0.5 (0.2, 0.9) 74 (79.6) 0.6 0.7 (0.3, 1.6) Breastfeeding duration
Gave index child formula while breastfeeding 68 (58.1) 78 (56.9) 1.0 0.9 (0.5, 1.5) 38 (54.3) 0.8 0.7 (0.4, 1.5) Mother ’s BMI at the start of pregnancy
Underweight (BMI:<18.5) 5 (3.5) 10 (5.4) 1.9 2.6 (0.7, 9.4) 8 (8.4) 3.8 4.5 (1.0, 20.1) Normal (BMI: 18.5- < 25) 90 (62.1) 101 (54.9) 1.0 Referent 50 (52.6) 1.0 Referent Overweight (BMI:25- < 30) 31 (21.4) 45 (24.5) 1.3 1.2 (0.7, 2.3) 20 (21.1) 1.3 1.2 (0.5, 2.6) Obese (BMI: ≥ 30) 19 (13.1) 28 (15.2) 1.4 1.1 (0.5, 2.5) 17 (17.9) 1.6 1.0 (0.4, 2.5) Weight gain in pregnancy
Low weight gain 23 (17.0) 26 (14.7) 0.9 0.8 (0.4, 1.8) 12 (13.0) 0.8 0.8 (0.3, 2.0)
High weight gain 61 (45.2) 87 (49.2) 1.1 1.1 (0.6, 1.8) 46 (50.0) 1.0 0.8 (0.4, 1.6) Father ’s BMI at the start of pregnancy
Underweight (BMI:<18.5) 1 (0.7) 2 (1.2) 2.8 2.2 (0.1,34.6) 2 (2.2) 3.2 3.1 (0.2, 47.5) Normal (BMI: 18.5- < 25) 36 (25.7) 33 (20.1) 1.0 Referent 32 (35.2) 1.0 Referent Overweight (BMI:25- < 30) 57 (40.7) 84 (51.2) 1.6 1.7 (0.9, 3.1) 33 (36.3) 0.7 0.7 (0.4, 1.5) Obese (BMI: ≥ 30) 76 (32.8) 45 (27.4) 1.1 1.0 (0.4, 1.9) 24 (25.4) 0.6 0.6 (0.3, 1.3) a
Adjusted for the matching variable, child ’s age at interview
b
Adjusted for the child ’s age at interview, mother’s race/ethnicity, mother’s educational attainment, and household income
Trang 7In the United States, 12 % of women ages 15–44
re-ceive infertility services at some point in their lives, and
1 % of children born each year are conceived through
assisted reproductive technologies [34] Although only a
small number of our study participants reported
hav-ing treatment for infertility, we observed a trend
to-wards increased risk for retinoblastoma with infertility
treatment In our California studies, we observed
in-creased cancer risk among the offspring of multiple
births, particularly among embryonal tumors; this
may support associations with infertility treatment [6,
35–37] Although the rarity of childhood cancer has
limited research in this area, studies suggest an
in-creased risk for childhood cancers among children
conceived after infertility treatments, including a
meta-analysis of four studies which observed increases
in risk for retinoblastoma (RR = 1.62) [4, 38] Possible
mechanisms that may explain this increased cancer
risk include epigenetic changes such as altered DNA
methylation and changes in chromatin structure,
which may cause imprinting disorders and modified
gene expression [39] However, there is debate as to
whether the source of any increased risk for
child-hood cancer may be the infertility treatment itself or
rather due to factors related to the underlying fertility
problems
While breastfeeding confers a number of health bene-fits to infants, it may also expose the newborn to ele-vated levels of varying exogenous chemicals that can be found in milk, such as pharmaceuticals taken by the mother, heavy metals, or volatile organic compounds [40] Our finding of a negative association with breast-feeding was not confirmed in dose–response analyses, which examined duration of breastfeeding Because we did not collect the reason that parents ceased breast-feeding, it is not known if case parents’ weaning was a result of the retinoblastoma diagnosis
We additionally observed an increased risk for retino-blastoma with maternal intake of prescription pain medication during pregnancy The majority of mothers who had taken medication reported intake of acetamino-phen (paracetamol) However, misclassification of expos-ure is a concern given that there were likely a considerable number of mothers in our study who took over-the-counter acetaminophen during their pregnan-cies In a pooled analysis of two large studies, 56 % of
US women reported taking acetaminophen while preg-nant [41] Despite that acetaminophen is a commonly recommended pain medication for use in pregnancy, there are reports of increased risk of adverse childhood health conditions such as preterm birth, asthma, and hyperkinetic disorders with acetaminophen use [42–44]
Table 4 Sporadic retinoblastoma in relation to the mother’s birth control use and fertility treatment
Controls Unilateral (n = 165) Bilateral (n = 87)
N (%) N (%) OR OR (95 % CI) N (%) OR OR (95 % CI) Birth control used in the year before the index pregnancy b
Any birth control 75 (52.5) 85 (46.6) 0.8 0.9 (0.5, 1.5) 45 (47.9) 0.8 0.7 (0.4, 1.4) Oral contraceptive pills 43 (29.3) 60 (32.4) 1.2 1.5 (0.8, 2.5) 28 (29.5) 0.8 0.8 (0.4, 1.6) Injection, Implant, skin patch, Vaginal ring 9 (6.1) 13 (7.0) 1.2 1.1 (0.4, 3.3) 7 (7.4) 1.0 0.9 (0.3, 3.5) Any hormonal contraceptive 49 (33.3) 71 (38.4) 1.3 1.5 (0.9, 2.6) 34 (35.8) 0.9 0.9 (0.5, 1.7)
Intra uterine device (IUD) 4 (2.7) 3 (1.6) 0.6 0.4 (0.1, 2.1) 1 (1.1) 0.4 0.4 (0.0, 4.8)
-Child conceived with the help of fertility treatment c
Any type of fertility treatment used by either parent 9 (6.3) 14 (7.7) 1.1 1.4 (0.5, 3.5) 8 (8.5) 1.2 1.5 (0.5, 4.5) Mother took fertility medication for this pregnancy 8 (5.6) 14 (7.6) 1.3 1.6 (0.6, 4.1) 6 (6.4) 1.0 1.2 (0.3, 4.1)
-Used artificial intrauterine insemination 2 (1.4) 3 (1.6) 1.1 1.3 (0.2, 8.3) 3 (3.2) 2.0 2.3 (0.3, 18.0) Used Intra Cytoplasmic Sperm Injection (ICSI) 1 (0.7) 3 (1.6) 1.9 2.0 (0.2, 23.3) 2 (2.1) 1.9 2.4 (0.2, 28.9) Problem with egg was the reason for infertility treatment 2 (1.4) 2 (1.1) 0.9 1.1 (0.1, 10.1) 4 (4.3) 2.9 4.0 (0.6, 29.0) Problem with sperm was the reason for infertility treatment 0 (0.0) 3 (1.6) - - 2 (2.1) - -The reason for infertility treatment was unknown 3 (2.1) 7 (3.8) 1.6 2.3 (0.6, 9.4) 2 (2.1) 0.8 1.3 (0.2, 9.1)
a Adjusted for matching variable, child’s age at interview
b
Adjusted for child’s age at interview, mother’s race/ethnicity, mother educational attainment, household income, and if the mother smoked in the month before and during pregnancy
c
Adjusted for child ’s age at interview, mother’s race/ethnicity, mother’s educational attainment, and household income
Trang 8A limitation of our study is the possibility of recall
errors In retrospective studies in which mothers are
queried about pregnancy health, mothers do best at
re-membering serious health conditions or major events
For example, hypertension, diabetes, and previous
still-births tend to be recalled quite accurately, while recall
of anemia is more moderate [45, 46] Mothers tend to
remember medications taken for chronic conditions
more accurately than those taken for only a short time
period [47], and accuracy in recall of short-term
medi-cation may differ between cases and controls [48]
However, maternal health conditions were reported in
our study at a similar prevalence to rates observed in
recent large-scale epidemiologic studies in the US and
elsewhere Pregnancy prevalence of chronic
hyperten-sion is 0.5–3 % and gestational hypertenhyperten-sion, 4–14 %
[49, 50]; chronic diabetes is 1–2 % and gestational
diabetes is 8 % [51]; asthma is seen in 4–9 % of US
preg-nant women [52] and hypothyroidism in 2–3 % [53] In
contrast, the prevalence of depression was much lower
in our study than has been seen in other US surveys
(10–12 % [54, 55]), potentially due to parental
interviewers
Another limitation in this study is the possibility of
selection bias in the form of overmatching Due to
the use of friend controls, it is likely that maternal
characteristics of cases and controls would be similar
However, differing response rates resulted in controls
who tended to be White, more educated, and of
higher SES In matched/conditional analyses, cases
without matched controls would drop out of the
ana-lysis, while unconditional analyses would need to be
controlled for these factors to mitigate the effect of
bias due to overmatching In our analyses, we
attempted to control for race, education, and SES,
though it may not have completely controlled for all
bias due to selection As a consequence, the forced
similarities between cases and controls are likely to
bias results to the null
Conclusion
In conclusion, we observed retinoblastoma to be
asso-ciated with several maternal medical conditions and
perinatal health-related behaviors There are few
internationally, and our results require replication
elsewhere, ideally in studies which utilize pharmacy or
medical records Although the public health impact of
these associations is likely to be small, our study raises
the possibility of several associations, and
confirm-ation of our observconfirm-ations may contribute to
preven-tion recommendapreven-tions for pregnant women
Additional file Additional file 1: Table S1 Multiple imputation/propensity score analysis of retinoblastoma in relation to maternal medical conditions and prescription drug use which occurred in the month before or during the pregnancy Table S2 Multiple imputation/propensity score analysis of associations between maternal pregnancy history, body size, and breastfeeding with retinoblastoma using unconditional logistic regression Table S3 Multiple imputation/propensity score analysis of sporadic retinoblastoma in relation to the mother ’s birth control use and fertility treatment (DOC 141 kb)
Competing interests The authors state that there is no conflict of interest with respect to the contents of this manuscript for any individual author.
Authors ’ contributions
AG and GB were responsible for the conception, study design, data collection and critical review of this manuscript SA and NO were responsible for data analysis and writing part of the manuscript JH was responsible for data interpretation, writing and editing the manuscript OE and BR were responsible for data interpretation and reading and revising drafts of the article All authors have read and approved the final version of this manuscript The authors are grateful to Dr Carol Shields of the Wills Eye Hospital, Thomas Jefferson University, Philadelphia and Children ’s Oncology group for contributing cases to this study.
Acknowledgements This work was supported in part by grants from NIH/NCI (RO1CA118580, R21CA175959), NIH/NIEHS (R03ES021643), and ARRA supplement (CA-118580-03S1) Dr Azary and Ms Omidakhsh were supported by a grant from the Jonsson Cancer Center Foundation/UCLA.
Author details
1
Department of Epidemiology, Fielding School of Public Health, University of California, 650 Charles E Young Dr, Box 951772, Los Angeles, CA 90095-1772, USA.2Department of Community Health Sciences, Fielding School of Public Health, University of California, 650 Charles E Young Dr, Box 951772, Los Angeles, CA 90095-1772, USA.3Division of Oncology and Center for Childhood Cancer Research, Children ’s Hospital of Philadelphia, 3535 Market Street, Room 1472, Philadelphia, PA 19104, USA.4Department of Genetics, University of Pennsylvania, USA415 Anatomy Chemistry Building, 3620 Hamilton Walk, Philadelphia, PA 19104, USA.
Received: 14 May 2014 Accepted: 10 October 2015
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